Polycystic Ovary Syndrome as a Risk Factor for Diabetes

PCOS Inhibits Regular Menstruation & Increases Risk of Diabetes

These days we hear a number of young girls and women complaining of irregular periods or prolonged absence of menstruation for even 3 months or so. Polycystic ovary syndrome (PCOS) is a common disorder among females characterized by hyperandrogenism, menstrual and ovulatory alterations and polycystic ovarian morphology. This is a condition that affects the woman’s ability to produce eggs causing a profound number of cysts to appear on the surface of the ovaries. The cysts are nothing but follicles that contain underdeveloped eggs which are often released at irregular intervals. In some, PCOS totally stops the release of eggs. Such conditions lead to irregular/loss of periods, weight gain, acne, thinning of hair, excessive hair growth in other parts of the body and fertility problems. But the effects of PCOS go beyond the reproductive boundary extending to insulin resistance, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Insulin resistance has been proposed as one of the key effects of PCOS resulting in reproductive as well as metabolic disturbances besides increasing the risk of cardiometabolic risk for women with PCOS. PCOS has been declared as a nonmodifiable risk factor for diabetes by the International Diabetes Federation & by the American Diabetes Association with evidence from observational, retrospective and short-term prospective studies. We don’t have much long-term studies identifying increased risk of T2DM in women with PCOS.
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Long-Term Prospective Study on Diabetes Risk in Women with PCOS
PCOS is very common affecting 1 in every 5 women at some point of life. Though its cause remains unknown its believed that higher than normal androgen levels play an important part besides other risk factors such as excess weight and family history, both of which are also risk factors for insulin resistance.

A long-term observational study on Italian women with PCOS was conducted for at least 10 years to evaluate the incidence rate of type 2 diabetes during the period. During the first examination between 1978 and 1999 every woman was screened for PCOS and in 2009, all of those having PCOS were asked to come for a follow-up examination during which the same set of tests as done during the first examination was performed. Even before the start of study those women with Cushing’s syndrome, androgen-secreting neoplasm, hyperprolactinemia, congenital adrenal hyperplasia, thyroid disease, or other causes of amenorrhea, including premature ovarian failure were excluded. All the women were questioned on their smoking, drug therapy and any history of diseases, their height, weight, waist circumference and blood pressure measurements were taken. Fasting blood samples were taken to measure levels of different hormones such as luteinizing and follicle-stimulating hormone, 17β-estradiol, testosterone, and sex hormone-binding globulin (SHBG). Blood samples were taken during the first week after start of menstruation and after withdrawal of bleeding and glucose tolerance test was performed too.

Results
After implementing various exclusion criteria, a total of 277 women were involved in the study from 1978 to 1999. All of them were once again contacted in 2009 for follow-up but 22 women were unavailable for data due to various reasons (death, some did not want to pursue further or had given birth to a child). The remaining 255 women were re-evaluated in 2009 and the information collected was used to compare between the rates of type 2 diabetes of women with PCOS and the general female population. 226 women with PCOS were regularly followed-up by the research team checking on their performance every 1-2 years. During the follow-up period 163 participants were on oral contraceptive treatment for at least a year, 72 were on metformin, 29 were on flutamide, 22 were on antihypertensive drugs and 4 were on statins. At baseline, there was no difference observed in any of the parameters with the exception of luteinizing hormone blood levels which was higher than normal in the participants.

It was observed that 6 women were diabetic at baseline and 42 women developed type 2 diabetes during the follow-up. 39.3% of the population suffered from type 2 diabetes at the end of follow-up that’s higher than the general population. The follow-up period of diabetic women was much longer than that of nondiabetic women and, diabetic women were much older comparatively. They also had higher BMI and larger waist circumference, higher fasting glucose and insulin levels and higher glucose but lower sex hormone binding globulin (SHBG) levels. It was observed that a greater number of women with diabetes were under metformin treatment during follow-up compared to oral contraceptive treatment when compared to women free of disease. The incidence rate of type 2 diabetes increased with increasing BMI, fasting glucose and glucoseAUC rates at baseline. Whereas, a higher SHBG level at follow-up was linked to a lower risk of developing type 2 diabetes.

When comparing the risk of T2DM with BMI levels it was seen that risk of diabetes steadily increased with BMI and was especially high when BMI≥30. Obesity is a common risk factor for PCOS, BMI values increase with increasing obesity rates and such high BMI levels and glucose rates contributed to increase in type 2 diabetes rates in women with PCOS. The study shows that risk of type 2 diabetes increased in women with PCOS during middle-age and hence it is required that women with PCOS are regularly screened for diabetes risk.

Diabetes Risk for Women with PCOS based on CARDIA Study
The coronary artery risk development in young adults (CARDIA) study was used for procuring study sample for diabetes risk in PCOS-affected women. The sample included 1127 women who were present both at Year 2 and Year 16 examinations with Year 2 examination considered to be the baseline for the study. Androgen values were obtained from Year 2 and Year 16; at year 16 the participants were queried about symptoms at two time frames, past (ages 20-30) and current (ages 34-46). All the women were questioned on the length and regularity of menstrual cycles. PCOS was reported by self-reporting symptoms such as oligomenorrhea, hirsutism and serum androgen measures. Participants having oligomenorrhea between 20-32 years of age and hirsutism between 20 and 30 years of age were classified as having PCOS. Women with PCOS were classified during two time frames: Year 2 (ages 20-32) and Year 16 (ages 34-46). Weight, height, BMI and waist circumference was measured. Participants were classified as ‘never PCOS’ when they did not fulfil the criteria for PCOS during both time frames, ‘early PCOS’ when they fulfilled Year 2 criteria only and ‘persistent PCOS’ when they fulfilled PCOS criteria at both time frames. Participants were branded as diabetic when fasting plasma glucose ≥126 or when they were using diabetes measurements.

Of the 1127 women only 53 of them met PCOS criteria at ages 20-32. While PCOS-affected and normal participants did not differ in BMI, waist circumference, physical activity, alcohol use and tobacco use it was seen that women with PCOS had higher mean fasting insulin levels and had not given birth to babies. Both groups of women did not differ in terms of presence of hypertension and diabetes. Results showed that women with PCOS at ages 20-32 were likelier to develop diabetes by the time they reached 38-50 years of age and it doubled the risk of diabetes. PCOS increased the risk of diabetes by as much as 3-folds in normal weight women with PCOS compared to normal weight women without PCOS. Only 2% women met criteria for persistent PCOS while 3.5% were classified as having ‘early PCOS’. Those with persistent PCOS had a 7-fold risk of developing diabetes in the next 5 years compared to those without PCOS while those with early PCOS did not show such risks.

Risk of Gestational Diabetes Due to PCOS
Gestational diabetes mellitus (GDM) is a common concern in pregnant women whose rates can be anywhere from 9-25%. GDM and PCOS are one of the most common endocrine disorders in women of reproductive age both of which relate to overweight/obesity and insulin resistance and they are also clear indications of T2DM risk. A Finnish study tried to prove that PCOS is an independent risk factor for GDM.

The Finnish Gestational Diabetes Study (FinnGeDi study) recruited a group of 1115 women with GDM and a singleton pregnancy who were about to deliver. Another set of 1125 women with no GDM giving birth in the same hospital were recruited as controls. After imposing exclusion criteria the research team was left with 1146 in the GDM group and 1066 women in the non-diabetic control group. All the participants were asked to fill a questionnaire about their medical and family history also involving questions on oligomenorrhoea, the presence of hirsutism and prior diagnosis of PCOS. A total of 1030 candidates with GDM and 935 non-diabetic women returned the questionnaire. GDM was diagnosed by a 2-h 75 g oral glucose tolerance test (OGTT) after overnight fasting. OGTT is generally performed between the 24th and 28th weeks of pregnancy but also can be done between 12th and 16th week when the woman is at a high risk of GDM.

521 women had irregular menses (oligomenorrhoea), 207 had hirsutism while 87 suffered from both. 124 of them reported prior diagnosis of PCOS and 37 reported prior diagnosis and two symptoms. This led to a total of 174 women with both symptoms and prior diagnosis to suffer from PCOS. The total study population of 1941 women were divided into four groups: GDM+PCOS (n=105), GDM+non PCOS (n=909), non-GDM+PCOS (n=69) and controls (n=858).

Results

1. 10.4% women with GDM and 7.4% non-diabetic women reported symptoms and diagnosis of PCOS
2. Participants born with a low birth weight had a higher risk of GDM irrespective of the presence of PCOS probably due to slower foetal growth.
3. Participants born preterm were twice at a risk of GDM
4. Participants with GDM irrespective of PCOS state were less educated, had higher pre-preganncy BMI, were older, had 3 or more previous pregnancies and were short.
5. Participants in the PCOS+GDM group had higher pre-preganncy BMI and likelier to be obese than those in the other three groups.
6. The participant’s risk for GDM was doubled when her mother had a history of GDM or T2DM. When the participant’s father had a history of T2D the participant’s risk for GDM was 1.4-fold.

This study concluded that PCOS is not an independent risk factor for GDM and the increased risk of GDM in women with PCOS is mainly linked to adiposity. Obese women with PCOS who are at an increased risk for GDM need insulin treatment during pregnancy.

References
Polycystic Ovary Syndrome is a Risk Factor for Type 2 Diabetes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425413/

Polycystic Ovary Syndrome & Risk for Long-term Diabetes & Dyslipidaemia: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060760/

Polycystic Ovary Syndrome & Risk Factors for Gestational Diabetes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026881/
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The Link between Polycystic Ovary Syndrome & Type 2 Diabetes: What Do We Know Today? https://www.openaccessjournals.com/articles/the-link-between-polycystic-ovary-syndrome-and-type-2-diabetes-what-do-we-know-today.pdf